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SMO variants explain the majority of drug resistance in basal cell carcinoma [RNA-Seq]

ABSTRACT: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms, providing a unique opportunity to study human tumor evolution. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs compared with 5.6% (2/36) of untreated BCCs (p<0.0001), and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket (LBP) mutations that define sites of inhibitor binding and four variants that confer constitutive activity and inhibitor resistance, thus defining pivotal residues of SMO that ensure receptor autoinhibition. Finally, we show that both classes of SMO variants respond to the aPKC-ι/λ inhibitor PSI and GLI2 antagonist ATO that operate downstream of SMO

ORGANISM(S): Homo sapiens

PROVIDER: GSE58375 | GEO | 2015/03/16

SECONDARY ACCESSION(S): PRJNA252377

REPOSITORIES: GEO

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SMO variants explain the majority of drug resistance in basal cell carcinoma [exome-seq]

Project description:Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms, providing a unique opportunity to study human tumor evolution. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs compared with 5.6% (2/36) of untreated BCCs (p<0.0001), and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket (LBP) mutations that define sites of inhibitor binding and four variants that confer constitutive activity and inhibitor resistance, thus defining pivotal residues of SMO that ensure receptor autoinhibition. Finally, we show that both classes of SMO variants respond to the aPKC-ι/λ inhibitor PSI and GLI2 antagonist ATO that operate downstream of SMO.

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GBM response to Smo and PI3K inhibitors

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